Environmental factors and lifestyle have profound effects in the initiation, promotion and progression of cancer. Our recent work on environmental enrichment (EE), a housing environment boosting mental health, has revealed a novel phenotype characterized by a robust reduction in adiposity, resistance to diet-induced obesity, lower leptin level, higher adiponectin level, enhanced immune functions, and marked inhibition in melanoma and colon cancer growth. One key underlying mechanism is the activation of the hypothalamic- sympathoneural-adipocyte (HSA) axis whereby the physical, social and cognitive stimulations provided in EE stimulate brain-derived neurotrophic factor (BDNF) expression in the hypothalamus leading to preferential sympathoneural activation of white fat. The elevated sympathetic drive activates adipocyte ss-adrenergic receptors inhibiting leptin expression and release, and thereby suppresses cancer growth. The long-term goal of this project is to further characterize the role of HSA axis in cancer development and progression. Specifically we propose to generalize HSA activation to additional cancer models particularly the cancers with the strongest association with obesity such as breast cancer, and evaluate its long-term preventive effects. In addition we plan to determine whether genetically activating HSA axis by BDNF gene therapy can alleviate obesity and inhibit tumor growth in melanocortin receptor 4 (MC4R) deficient mice. Moreover we will evaluate whether long-term BDNF gene therapy using an autoregulatory vector can prevent the premature mortality in MC4R mice, a model representing the most common monogenic form of obesity. These studies will further characterize the HSA axis, elucidate underlying mechanisms, identify potential therapeutic targets, and provide the preclinical data to assess the potential to ultimate clinical intervention for cancer.